17(20)-enol-21-aldehydes of the pregnane series



United States Patent 3,255,218 17(20)-ENGL-21-ALDEHYDES OF THE PREGNANESERIES Hershel L.. Herzog, Mountain View, N.J., assignor to ScheringCorporation, Bloomfield, N.J., a corporation of New Jersey No Drawing.Filed Mar. 28, 1962, Ser. No. 183,033

18 Claims. (Cl. 260397.45)

This invention relates to compositions of matter classifiable in thefield of chemistry as steroidal enol aldehydes. More particularly, thisinvention relates to novel steroidal l7(20)-enol-21-aldehydes, to theprocess for their preparation, and to the method of employing thesecompounds as intermediates in the preparation of valu abletherapeutically active glucoand mineralocorticoids and progestationalagents.

The subject matter which applicant regards as his invention is describedas residing in the discovery that the 17u,2l-dihydroxy-20-keto sidechain attached at position 17 in steroids of the pregnane series isreadily rearranged by heating the appropriate steroid in solution in aweak acid. The product which results in each case now bears the17(20)-enol 2'l-aldehyde side chain and belongs to a heretofore ratherinaccessable class of steroid compounds.

These enol aldehydes are reactive compounds which,

for example, are reduced readily by the action of zinc and a weak acidto the corresponding Zl-hydroxy-ZO ketosteroids. This latter functionalsystem is characteristic of the physiologically important group ofmineralocorticoids such as, for example, desoxycorticosterone,corticosterone and aldosterone which maintain mineral balance in manymammalian species, including man.

In addition, the enol aldehydes of this invention are readily convertedinto the corresponding -lower alkanoyl enol esters by treatment with alower alkanoic acid anhydride in pyridine. When subjected to reductionby the action of zinc and a weak acid these esters yield thecorresponding 17(20)-enol-20-acylates as distinguished from the2l-hydroxy-20-keto steroids produced by the similar reduction of parentenol aldehyde. The 17 (20)- enol-ZO-acylates so produced can beconverted by .conventional techniques into the corresponding21-desoxy-20- ketosteroids, which functional system is characteristic ofsuch physiologically important progestational agents as progesterone andits llfi-hydroxy and ll-keto derivatives.

Neither the process of rearrangement, nor the conversion of the enolaldehyde into the corresponding ZO-enol ester, nor the reduction of theenol aldehyde or its 20- enol ester derivative is in any way inhibitedby alterations in rings A, B or C of the steroid. For example, A-unsaturation may be present or absent; there may be a hydroxyl or ketogroup at position 3; n -unsaturation may be present or absent; the6-position may carry a lower alkyl substituent; the 9-position .may behalogenated; the

ll-position may be unsubstituted or carry a hydroxyl or keto group; andposition 16 may carry a lower alkyl substituent. Typical variations instarting material structure and the products obtained therefrom may beillus trated as follows:

CHzOI-I wherein-Z may be 0, (H, oc-OH) or (H, B-OH); V may be H or loweralkyl; Y may be H, chlorine or fluorine; X may be H 0 or (H, B-OH); Wmay be H or lower alkyl; A is lower alkanoyl; and wherein Z cannot be(H, OH) when both double bonds are in the A-ring.

The rearrangement is usually carried out by refluxing a dilute solutionof the steroid in acetic acid for from 1-8 hours, preferably in thepresence of zinc acetate dihydrate which acts a's a catalyst. The acidmay be any lower fatty acid of which the most preferred are thoseboiling below C. Other zinc salts may be used as catalysts, the hydratedsalts of lower fatty acids being preferred. The optimum reaction timewill vary with the steroidal substrate and with the lower fatty acid butis usually within the range mentioned above with from 24 hours suificingfor most compounds.

Patented June 7, 1966 The enol aldehyde reaction product is isolated byremoving the solvent acid 'by distillation in vacuo, or by evaporation,followed by chromatography of the acid-free residue over a magnesiumsilicate such as Florisil. The solvent required to elute the enolaldehyde will vary with the degree of oxygenation of the steroid.Usually meth' ylene chloride or mixtures of alcohols such as methanol orethanol and the like with methylene chloride will effect the desiredseparation. The first eluates from the column which crystallize usuallycontain the enol aldehyde.

The conversion of enol aldehydes into the corresponding 20-loweralkanoic enol esters is conveniently carried out by dissolving the enolaldehyde in pyridine and adding thereto the desired lower alkanoic acidanhydride. Organic bases other than pyridine may vbe employed.Particularly desirable bases are the tertiary nitrogen bases and sodiumacetate. The reaction may also be carried out in the presence ofcatalytic quantities of p-toluene sulfonic acid. After the addition ofthe anhydride, the reaction mixture is held at room temperature for aperiod of from 8 hours to 3 days. The ester is precipitated by additionof water and recovered by filtration. While the optimum reaction timewill vary with the nature of the reactants,-an overnight period isusually suflicient.

The enol aldehyde products show a characteristic absorption in theultraviolet in the range of from 260-280 me which as a rule is notpresent in the parent steroid. The corresponding 20-lower alkanoyl enolesters have a characteristic band in the infrared at 5.655.70,u and showenhanced ultraviolet absorption in the 240-250 m region, withdisappearance of the band in the 260280 mm region.

Among the enol aldehydes of particular interest which may be preparedaccording to the process of this invention are the 6a-methyl substitutedderivatives of the preceding compounds, and the 1611- and 16,8-rnethylderivatives thereof.

As may be seen from the above description, the disclosed processes areof general application and may be used to convert17a,2l-dihydroxy-20-keto pregnanes broadly into 17(20)-enol-21-aldehydesand to the corresponding 20-enol esters. Among the enol aldehydes andenol esters so produced are many novel compounds, heretofore unknown,which applicant considers to be embraced within the scope of hisinvention and which are illustrated by the following structuralformulae:

0 II C- l M W HO MN W and the A and A -dehydro analogs thereof wherein Zmay be 0, (H, aOH) or. (H, 50H); V may be H or lower alkyl; Y may be H,chlorine or fluorine; Q may be chlorine or fluorine; X may be H or O; Wmay be H or lower alkyl; U is lower alkyl; R may be H or lower alkanoyl;and wherein Z is 0 when both double bonds are present in the A-ring.

Reduction of the above, as well as other l7(20)-enol- Zl-aldehydesyields potent glucoand mineralocorticoids. Thus, for example, thecompound 4-pregnene-17a,2l-diol 3,20-dione may be refluxed with glacialacetic acid in the presence of zinc diacetate dihydrate to give4,17(20)- pregnadiene-20-ol-21-al-3-one. This enol aldehyde may then bereduced under very mild conditions, such as for example with zinc andacetic acid or with lithium aluminum-trit-t-butoxyhydride intetrahydrofuran, to yield 4-pregnadiene-21-ol-3,20-dione(desoxycorticosterone), a potent mineralocorticoid.

Reduction of the above, as well as other, l7(20)-enol-2l-aldehyde-20-esters by methods previously discussed yields thecorresponding ZI-desoxy enol esters which may be subsequently convertedby conventional techniques into valuable progestational agents. Forexample, 4, 17(20)-pregnadiene-20-ol-2l-al-3-one, as prepared in thepreceding paragraph, may be treated with acetic anhydride in pyridine togive 4,17(20)-pregnadiene-20-ol-2lal-3-one -20-acetate which, whentreated. with zinc and acetic acid, is converted into4,l7(20)-pregnadiene-20- ol-3-one 20-acetate. Hydrolysis of thiscompound, using for example, alcoholic potassium hydroxide, yields 4-pregnene-3,20-dione (progesterone). As can be seen from the above, thisseries of reactions not only affords a novel synthesis of importantprogestational agents, but represents a method for simplifyingside-chain structure by removal of 17 and ZI-hydroxyl groups which maybe useful in structure problems arising from the microbiologicaltransformation of steroids.

The best mode contemplated "by the inventor for carrying out hisinvention will now be described as follows:

EXAMPLE 1 1,4,1 7 (20 -pregnatriene-20-0I-21 -al-3-0ne Heat at refluxfor six hours a solution of 2.0 gm. ofl,4-pregnadiene-17a,21-diol-3,20-dione in 200 ml. of glacial aceticacid. Cool to room temperature and concentrate by evaporation to aresidue. Take up the residue in methylene chloride, wash free of aceticacid with water, dry and concentrate the resulting solution to a smallvolume. Chromatograph the solution over 50 gm. of Florisil and elutewith methylene chloride. Crystallize the eluate and purify byrecrystallization from acetone-hexane.

EXAMPLE 2 I ,4 ,1 7 (20 -pregnatriene-20-0l-21-al- 3-0ne ZO-acetateDissolve 0.10 gm. of 1,4,l7(20)-pregnatriene-20-ol-2lal-3-one (thecompound of Example 1) in 1 ml. of pyridine. Add 1 m1. of aceticanhydride and allow the mixture to stand at room temperature forsixty-four hours. Add excess water and remove the precipitate byfiltration. Recrystallize from ether-hexane.

. EXAMPLE '3 4,17(20)-pregnadiene-11fl,20-di0l-21-al-3-one Heat atreflux for two hours a solution of 10.0 gm. of 4-pregnene-115,17a,2l-triol-3,20-dione in 400 ml. of glacial acetic acid, containing1.0 gm. of zinc acetate dihydrate. Cool the mixture to room temperatureand concentrate by evaporation. Extract the residue with methylenechloride and wash the extract free of acetic acid with water. Dry theextract, concentrate and chromatograph over 50 mg. of 'Florisil. Elutewith ether, crystallize the eluate and purify by recrystallization fromether-hexane.

EXAMPLE 4 4,1 7(20)-pregnaa'iene-11,6,20-diol-21-al'3- one ZO-acetateMix 0.50 gm. of 4,17(20)-pregnadiene-115,20-diol-21- al-3-one (thecompound of Example 3) with 5 ml. of pyridine and 5.0 ml. of aceticanhydride. Store at room temperature overnight. Add ice water andseparate the precipitate by filtration. Recrystallize fromacetonehexane.

EXAMPLE 5 1,4,1 7 (20) -pregnatriene-1 1,8,20-(11'01-21 -al-3-0ne Refluxfor two hours a solution of 9.95 gm. of1,4-pregnadiene-l15,l7a,2l-triol-3,20-dione in 400 ml. of glacial aceticacid containing 1.0 gm. of zinc acetate dihydrate. Cool the mixture andconcentrate by evaporation. Dissolve the residue in methylene chloride,wash free of acetic acid with water, dry and concentrate to a smallvolume. Chromatograph over 50 gm. of Florisil and elute with ether.Crystallize the eluate and purify by recrystallization fromacetone-hexane.

EXAMPLE 6 1,4, 1 7(20) -pregnatriene-115,20-dil-21-al- 3 -one 20-acetate Store at room temperature overnight a solution of 2.0 gm. of1,4,17(20)-pregnatriene-l15,20-diol-21-al-3- one (the compound ofExample in 20.0 ml. of pyridine and 20.0 ml. of acetic anhydride. Addexcess water and ice and remove the solvents in an air draft at roomtemperature. Recrystallize the residue from acetonehexane.

EXAMPLE 7 Employ the method of any of Examples 1, 3 or 5, to make thefollowing conversions:

to 4,l7(20)-pregna- 69a-fluoro-6a-methyl-4-pregnene-17a,21-diol-3,l1,20-

trione to 9a-fluoro-6a-methyl-4J7(20)-pregnadiene- 20-01-2 l-al-3,ll-dione 9a-fiuoro-6(3-methyl-4-pregnene-17a,2l-diol-3,l 1,20- trione to9a-fluoro-6fl-methyl-4,l7 (20)-pregnadiene- 20-ol-2l-al-3,l l-dione9a-fluoro-6a-methyl-4 pregnene-l15,l7a,21-triol-3,20- dione to9a-fluoro-6a-methyl-4J7(20) -pregnadiene- 116,20-diol-21-al-3-onel6a-methyl-1,4-pregnadiene-17a,2l-diol-3,20-dione to16a-methyl-1,4,17(20)-pregnatriene-20-ol-2Lal-S-one9a-fluoro-l6fi-methyL4-pregnene-l711,21-diol-3,1 1,20-

trione to 9a-fluoro-l6fi-methyl-4,l7(20)-pregnadiene- 20-01-2 1-al-3,1l-dione S a-fluoro-l6a-methyl-4-pregnene-l7a,2l-di-ol-3,l1,20-

trione to '9a-fluoro-16a-methyl-4,17(20) -pregnadiene--20-ol-21-al-3,11-dione 9a-fluoro-16fi-methyl-4-pregnene-l1fi,17a,21-iIiOl-3,20-

dione to 9a-fiuoro-l65-methyl-4,17(20) -pregna'diene-115,20-diol-21-al-3-one 9ot-fillOl'O-16a-II16ihYl-4 pregnene-11p,17a,2ltrial-3,20- dione to 9a-fluoro-l6a-methyl-4,17(20) pregnadiene- 115,20-diol-21-al-3-one 9a-fiuoro l6'B-methyl 1,4-pregnadiene 1741,21diol- 3,11,20-trione to 9a-fiuoro 16B-methyl 1,4,17(20)-pregnatriene-20-ol-2 l-al-3 ,1 l-dione 9a-fiuoro 16a-methyl1,4-pregnadiene 17a,21 diol- 3,11,20-tri0ne to 9a-fluoro 16ot-methyl1,4,l7(20)- pregna-triene-20-ol-2l-al-3,1 l-dione 3,20-dione to9u-fluoro-l6 8-methyl-1,4,17(20) pregnatriene-l 1,8,20-diol-21-al-3-one9a-flUOIO-16oc-IflfithYI-L4 pregnadiene-ll/8,17a,21-triol- 3,20-dione to9rxruoro 16m-methyl-1,4,17(20) -pregnatriene-l 15-20-dio1-2 l-al-3-oneEXAMPLE 8 Employ the method of any of Examples 2, 4 or 6, to convert anyof the enol aldehydes of Example 7 into the coresponding ZO-acetates.Where desired, replace the acetic anhydride with any lower alkanoic acidanhydride.

EXAMPLE 9 Conversion of 1,4,17(20) -pregnatriene-20-0l -21-al-3- one into 1-dehydrodes0xyi:orticosterone To a solution of 0.04 gm. of1,4,l7(20)-pregnatriene 20-ol-21-al-3-one in 10.0 ml. of anhydroustetrahydro furan at 0 C. add 0.035 gm. of lithiumaluminum-trit-butoxyhydride. Agitate the mixture for thirty minutes at 0C. and allow the temperature to rise to room temperature. Add Water andextract with methylene chloride. Dry the extracts and concentrate byevaporation. chromatograph over 3.0 gm. of Florisil and elute with 1%methanolmethylene chloride. Crystallize the eluate and purify byrecrystallization from acetone-ether.

EXAMPLE 10 Conversion of 4,17(20) -pregnadiene-11,8,20-di0l-21-al-3- oneinto corticosterone To a solution of 1.0 gm. of 4,17(20)-pregnadiene-11,8,20-diol-21-al-3-one in 25.0 ml. of acetic acid add 25.0 ml. ofwater and 10.0 gm. of granular zinc. Agitate the mixture at 30-35 C. forfour hours. Remove the zinc by filtration and wash with 50% aqueousacetic acid. Combine the filtrates, concentrate in an air draft and addexcess water. Extract with methylene chloride. Wash the extract withwater, dry and concentrate to a residue. Recrystallize the residue fromacetone-hexane.

7 EXAMPLE 11 Conversion of 4,1.7(20)-pregnadiene-115,20-di0l-21-al-3-one 20-acetate into 11 -ketoprogesterone (A) 4,17 20)PREGNADIENE-l1B,20-DIOL 3-ONE ZO-ACETATE To a solution of 0.325 gm. of4,l7(20)-pregnadiene- 115,20-diol-21-a1-3-one 20-acetate in 15.0 ml. ofacetic acid add 15.0 ml. of water and 3.0 gm. of zinc granules. Agitateat 3035 C. for four hours. Remove the zinc by filtration and wash with50% aqueous acetic acid. Combine the filtrates, concentrate byevaporation and add excess water. Extract with methylene chloride, washthe extract with water, dry and concentrate to a residue. Dissolve theresidue in hexane containing a small quantity of methylene chloride andchromatograph over 7 gm. of Florisil. Elute with 50% ether-hexane,crystallize the eluate and purify by recrystallization fromacetonehexane.

(B) llfi I'IYDROXYPROGESTERONE Store at 27 C. for two hours a solutionof 0.09 gm. of 4,l7(20)-pregnadiene-11,6,20-diol-3-one ZO-acetate in 5.0ml. of methanol and 1.0 ml. of methauolic potassium hydroxide. lute withwater. Extract with methylene chloride, Wash the extract with water, dryand concentrate to a residue. Recrystallize from acetone-hexane.

(C) ll-KETOPROGESTERONE To a solution of 0.05 gm. ofllfihydroxyprogesterone in 2 ml. of acetic acid add 0.011 gm. of chromicacid of 0.5 ml. of water. After three hours storage at room temperature,add excess water and extract with ether. Wash the extract, dry,concentrate and crystallize by the addition of hexane.

I claim:

1. A process for the preparation of steroidal 17-enol- 2l-aldehydeswhich comprises refluxing a steroidal substrate of the pregnane serieshaving a molecular structure in which an a-hydroxyl group is attached tothe 17- position, a keto group is attached to the 20-position and ahydroxyl is attached to the 2l-position with an anhydrous lower fattyacid and isolating the 17(20)-en0l- 21-aldehyde so produced.

2. The process of claim 1 wherein the anhydrous lower fatty acid has aboiling point below 150 C.

3. The process of claim 1 wherein the anhydrous lower fatty acid isacetic acid.

4. The process of claim 1 wherein the reaction is car- I ried out in thepresence of a catalytic quantity of a member of the group consisting ofzinc salts of lower fatty acids.

5. The process of claim 4 wherein the zinc salt is zinc acetatedihydrate.

6. Compounds selected from the group consisting of pregnanes having thefollowing structural formulae:

Make the reaction mixture acid and diand the 1,2-dihydro analogs thereofwherein V is a member of the group consisting of H and lower alkyl; Y isa member of the group consisting of chlorine and fluorine; W is a memberof the group consisting of H and lower alkyl; R is a member of the groupconsisting of H and lower alkanoyl; and X is a member of the groupconsisting of O and (H, (30H).

7. 4,17(20)-pregnadiene-20-ol-21-al-3-one.

8. 1,4,17(20)-pregnatriene-20-ol-21-al-3-one.

9. 9a-fiuoro-4,17(20) pregnadiene-l15,20-diol-21-al- 3-one.

10. 9u-fluoro-l,4,l7(20)-pregnatriene-115,20 diol-2lal-3-one.

11. 9a-fiuoro 16a-methyl-4,17(20)-pregnadiene-20-ol- 2l-al-3,11-dione.

12. 9u-fiuoro-16a-methyl-L4,17(20) pregnatriene-ZO- ol-2l-al-3,11-dione.

13. 9a-fluoro-l6;3-methyl-1,4,17(20) pregnatriene-ZO-ol-21-al-3,11-dione.

113,20-diol-2 l -a1-3 -one.

18. 9a-fluoro-16/3 methyl-4,17 (20) pregnadiene-ZO- ol-2l-al-3,11-dione.

References Cited by the Examiner UNITED STATES PATENTS 6/1957 Beyler260-397.45 6/1958 Nobile 51 OTHER REFERENCES Beyler et a1. J.A.C.S.,vol. 79, pp. 5297-5300 (1957). Herzog et al., J.A.C.S., vol. 83, pp.4073-4076 (Oct. 5, 1961).

LEWIS GOTTS, Primary Examiner.

G. F. LANDE, Assistant Examiner.

6. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF PREGNANES HAVING THEFOLLOWING STRUCTURAL FORMULAE: